title: Epigenetic pathways and glioblastoma treatment.
abstract: Glioblastoma multiforme (GBM) is the most common malignant adult brain tumor. Standard GBM treatment includes maximal safe surgical resection with combination radiotherapy and adjuvant temozolomide (TMZ) chemotherapy. Alarmingly, patient survival at five-years is below 10%. This is in part due to the invasive behavior of the tumor and the resulting inability to resect greater than 98% of some tumors. In fact, recurrence after such treatment may be inevitable, even in cases where gross total resection is achieved. The Cancer Genome Atlas (TCGA) research network performed whole genome sequencing of GBM tumors and found that GBM recurrence is linked to epigenetic mechanisms and pathways. Central to these pathways are epigenetic enzymes, which have recently emerged as possible new drug targets for multiple cancers, including GBM. Here we review GBM treatment, and provide a systems approach to identifying epigenetic drivers of GBM tumor progression based on temporal modeling of putative GBM cells of origin. We also discuss advances in defining epigenetic mechanisms controlling GBM initiation and recurrence and the drug discovery considerations associated with targeting epigenetic enzymes for GBM treatment.
authors.affiliation: Division of Biostatistics; Department of Epidemiology and Public Health; University of Miami Miller School of Medicine; Miami, FL USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Clarke
authors.forename: Clara
authors.initials: C
authors.lastname: Penas
authors.forename: Chiara
authors.initials: C
authors.lastname: Pastori
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Komotar
authors.forename: Amade
authors.initials: A
authors.lastname: Bregy
authors.forename: Ashish H
authors.initials: AH
authors.lastname: Shah
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
authors.forename: Nagi G
authors.initials: NG
authors.lastname: Ayad
mesh_terms: D000328:Adult; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D055808:Drug Discovery; D044127:Epigenesis, Genetic; D053263:Gene Regulatory Networks; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000628:therapy; D049490:Systems Biology; D000077204:Temozolomide
chemical_list: D003606:Dacarbazine; D000077204:Temozolomide
keywords: drug discovery; epigenetics; glioblastoma; statistical modeling